A randomized trial comparing standard versus high-dose daunorubicin induction in patients with acute myeloid leukemia

We conducted a phase 3 randomized trial comparing 2 different doses of daunorubicin as induction chemotherapy in young adults (60 years of age or younger) with acute myeloid leukemia (AML). Of 383 patients who were analyzed, 189 received standard-dose daunorubicin (SD-DN, 45 mg/m2 per day times 3 days) and 194 received high-dose daunorubicin (HD-DN, 90 mg/m2 per day times 3 days) in addition to cytarabine (200 mg/m2 per day times 7 days) to induce complete remission (CR). The CR rates were 72.0% in the SD-DN arm and 82.5% in the HD-DN arm (P = .014). At a median follow-up of 52.6 months, overall (OS) and event-free (EFS) survival were higher in the HD-DN arm than in the SD-DN arm (OS, 46.8% vs 34.6%, P = .030; EFS, 40.8% vs 28.4%, P = .030). Differences in CR rate and both OS and EFS remained significant after adjusting for other variables (CR, hazard ratio [HR], 1.802, P = .024; OS, HR, 0.739, P = .032; EFS, HR, 0.774, P = .048). The survival benefits of HD-DN therapy were evident principally in patients with intermediate-risk cytogenetic features. The toxicity profiles were similar in the 2 arms. In conclusion, HD-DN improved both the CR rate and survival duration compared with SD-DN in young adults with AML. This study is registered at www.clinicaltrials.gov as #NCT00474006.     

Salvage treatment for primary resistant acute myelogenous leukemia consisting of intermediate-dose cytosine arabinoside and interspaced continuous infusions of idarubicin: A phase-II study (no. 06901) of the EORTC Leukemia Cooperative Group

 Twenty-one patients with acute myeloid leukemia (AML) who failed to enter complete remission (CR) after first-line standard-dose remission-induction therapy with 7 days of cytarabine and 3 days of daunorubicin were treated with a salvage regimen containing intermediate-dose cytosine arabinoside (Ara-C) 2×500 mg/m²/day during 7 days in combination with continuous infusions of idarubicin 12 mg/m²/day on days 1, 3, and 5. Twenty patients were considered primary resistant, and one patient had a partial remission after two remission-induction courses. Overall, 11 patients (52%, 95% confidence interval: 30–74%) entered CR. Three patients died during hypoplasia and seven patients had resistant disease or a partial remission. The remission rate in this study compares favorably with the results obtained in similar patient categories. The toxicity of this salvage regimen was remarkably mild. No extramedullary toxicity was observed except for hepatic dysfunction in seven patients. The median duration of remission was 8.5 months, and ultimately, all complete remitters have relapsed except the patient who died from infectious complications after allogeneic bone marrow transplantation (BMT). This study shows that new intensive chemotherapy regimens may be effective after failure of primary treatment. Salvage regimens containing intermediate/high-dose Ara-C and/or alternative anthracyclines or anthracenes should be induced in the treatment of young patients with de novo AML. Received: 12 September 1995 / Accepted: 24 November 1995     

Activating mutations of RTK/ras signal transduction pathway in pediatric acute myeloid leukemia

Activating mutations of receptor tyrosine kinases (RTKs) and their downstream affectors are common in acute myeloid leukemia (AML). We performed mutational analysis of FLT3, c-kit, c-fms, vascular endothelial growth factor (VEGF) receptors (Flt-1, KDR [kinase domain receptor]), and ras genes in a group of 91 pediatric patients with AML treated on Children's Cancer Group clinical trial CCG-2891. Forty-six percent of patients had activating mutations of FLT3 (24.5%), c-kit (3%), or ras (21%) genes. Mutation-positive patients had a higher median diagnostic white blood cell (WBC) count (71.5 vs 19.6 x 10(9)/L; P =.005) and lower complete remission rate (55% versus 76%; P =.046) than mutation-negative patients. The Kaplan-Meier estimate of overall survival (OS) for patients with and without an activating mutation was 34% versus 57%, respectively (P =.035). However, within this group, patients with FLT3/ALM (activation loop mutation) had good outcomes (OS, 86%). Exclusion of the FLT3/ALM from analysis decreased the OS for the remaining mutation-positive patients to 26% (P =.003). Ten of the 23 mutation-positive and 11 of the 34 mutation-negative patients received an allogeneic bone marrow transplant (BMT) in first complete remission (CR). In the mutation-positive group, the disease-free survival (DFS) for the allogeneic BMT recipients was 72% versus 23% for the 13 patients who received chemotherapy or autologous BMT (P =.01). DFS for the mutation-free patients with and without allogeneic BM transplantation was 55% and 40%, respectively (P =.38). Activating mutations in the RTK/ras signaling pathway are common in pediatric AML, and their presence may identify a population at higher risk of poor outcome who may benefit from allogeneic BM transplantation.     

The value of fludarabine in addition to ARA-C and G-CSF in the treatment of patients with high-risk myelodysplastic syndromes and AML in elderly patients

Fludarabine in addition to cytosine-arabinoside (ARA-C) increases the accumulation of ARA-C-5'-triphosphate (ARA-CTP), which is responsible for the cytotoxic effect in leukemic blasts. In a randomized phase 3 trial, patients with high-risk myelodysplastic syndrome (MDS) (n = 91) or elderly patients with acute myeloid leukemia (AML) (n = 43) were randomized to receive 2 induction courses consisting of ARA-C (2 g/m2 days 1 through 5) and granulocyte colony-stimulating factor (G-CSF) (filgrastim, 5 microg/kg) during and after chemotherapy with or without fludarabine (25 mg/m2, days 1 through 5) (FLAG versus AG). Consolidation consisted of daunorubicin (45 mg/m2, days 1 through 3) and ARA-C (200 mg/m2, days 1 through 7). Complete remission (CR) rate following AG was 65% versus 71% with FLAG (P =.49). Overall survival (OS) at 24 months was 24% for AG treatment and 39% for FLAG (P =.32). Event-free survival (EFS) at 2 years was 10% and 19% (P =.31) for the AG and FLAG treatments, respectively. Platelet and granulocyte recovery times after the second cycle were prolonged in the FLAG treatment group. Grades 3 to 4 neurotoxicities were more often reported in the FLAG arm (14% versus 3%, P =.03), whereas no significant differences in other toxicities were observed. In a cohort of patients, the in vivo accumulation of ARA-CTP in leukemic cells was determined. Although ARA-CTP accumulation in leukemic cells after FLAG was enhanced, clinical outcome in terms of CR rate, OS, EFS, and disease-free survival (DFS) was not significantly improved by combining fludarabine with ARA-C.     

Randomized use of cyclosporin A (CsA) to modulate P-glycoprotein in children with AML in remission: Pediatric Oncology Group Study 9421

Relapse is a major obstacle in the cure of acute myeloid leukemia (AML). The Pediatric Oncology Group AML Study 9421 tested 2 different strategies to improve event-free survival (EFS) and overall survival (OS). Patients were randomized to receive standard-dose DAT (daunorubicin, cytarabine, and thioguanine) or high-dose DAT during induction. To interfere with P-glycoprotein (P-gp)-dependent drug efflux, the second randomization tested the benefit of cyclosporine (CsA) added to consolidation chemotherapy. Of the 282 children randomly assigned to receive standard DAT induction, 248 (87.9%) achieved remission compared to 253 (91%) of the 278 receiving high-dose DAT (P = ns). Children with HLA-identical sibling donors who achieved a complete remission received an allogeneic bone marrow transplant as consolidation. For the 83 patients receiving a matched related donor bone marrow transplantation (BMT), the 3-year disease-free survival (DFS) is 67%. Of the 418 children who achieved remission and went on to consolidation with and without CsA, the DFS was 40.6% and 33.9%, respectively (P = .24). Overexpression of P-gp was infrequent (14%) in this pediatric population. In this study, intensifying induction with high-dose DAT and the addition of CsA to consolidation chemotherapy did not prolong the durations of remission or improve overall survival for children with AML.     

Myeloablative allografting for chronic lymphocytic leukemia: evidence for a potent graft-versus-leukemia effect associated with graft-versus-host disease

In all, 30 patients with CLL proceeded to myeloablative allogeneic BMT using related (n=20, 67%) or unrelated (n=10) donors, at the Princess Margaret Hospital (Toronto) (n=20) or the Leukemia/BMT Program of BC (Vancouver) (n=10), from 1989 to 2001. Median (range) interval from diagnosis to BMT was 4.8 (0.3-13) years, median number of prior therapies was three and median age 48 years. The preparative regimen included total body irradiation in 15 (50%). In all, 14 of 30 patients (47%) are alive, with median (range) follow up of 4.3 (2.4-10.5) years. All are in complete remission, two following therapy for post-BMT progression. Actuarial overall (OS) and event-free survival (EFS) at 5 years is 39% (OS 48% for related donor and 20% for unrelated donor BMT); cumulative incidence of nonrelapse mortality (NRM) and relapse is 47 and 19%, respectively. Both acute (RR=0.008, P=0.01) and chronic (RR=0.006, P=0.02) Graft-versus-host disease (GVHD) were associated with markedly decreased risk of relapse. Patients receiving grafts from unrelated donors had increased NRM (RR=3.6, P=0.02) and decreased OS (RR of death=3.4, P=0.002). Allogeneic BMT has resulted in long-term EFS in approximately 40% of patients with CLL. There is evidence for a strong graft-versus-leukemia effect associated with acute and chronic GVHD, resulting in near complete protection from relapse.     

Overall and event-free survival are not improved by the use of myeloablative therapy following intensified chemotherapy in previously untreated patients with multiple myeloma: a prospective randomized phase 3 study

We compared the efficacy of intensified chemotherapy followed by myeloablative therapy and autologous stem cell rescue with intensified chemotherapy alone in patients newly diagnosed with multiple myeloma. There were 261 eligible patients younger than 66 years with stage II/III multiple myeloma who were randomized after remission induction therapy with vincristine, adriamycin, dexamethasone (VAD) to receive intensified chemotherapy, that is, melphalan 140 mg/m(2) administered intravenously in 2 doses of 70 mg/m(2) (intermediate-dose melphalan [IDM]) without stem cell rescue (n = 129) or the same regimen followed by myeloablative therapy consisting of cyclophosphamide, total body irradiation, and autologous stem cell reinfusion (n = 132). Interferon-alpha-2a was given as maintenance. Of the eligible patients, 79% received both cycles of IDM and 79% of allocated patients actually received myeloablative treatment. The response rate (complete remission [CR] plus partial remission [PR]) was 88% in the intensified chemotherapy group versus 95% in the myeloablative treatment group. CR was significantly higher after myeloablative therapy (13% versus 29%; P =.002). With a median follow-up of 33 months (range, 8-65 months), the event-free survival (EFS) was not different between the treatments (median 21 months versus 22 months; P =.28). Time to progression (TTP) was significantly longer after myeloablative treatment (25 months versus 31 months; P =.04). The overall survival (OS) was not different (50 months versus 47 months; P =.41). Intensified chemotherapy followed by myeloablative therapy as first-line treatment for multiple myeloma resulted in a higher CR and a longer TTP when compared with intensified chemotherapy alone. However, it did not result in a better EFS and OS.     

Phase II study of 2-chlorodeoxyadenosine plus idarubicin for children with acute myeloid leukaemia in first relapse: a paediatric oncology group study

Relapse remains the leading cause of death in patients with acute myeloid leukaemia (AML). Relatively few new chemotherapy agents have been proven to be effective in this population. We report on a Phase 2 clinical trial using the novel combination of 2-chlorodeoxyadenosine (2-CDA) (8 mg/m2 per d x 5 d) plus idarubicin (Ida) (10 mg/m2 per d x 3 d). The study involved 109 paediatric patients with AML at first relapse, of whom 104 were available for analysis. The overall response rate was 51% (complete response [CR] + partial response) with a CR rate of 46%. 2-year event-free survival (EFS) and overall survival (OS) were 20% and 26%. The only significant variable in determining response, EFS and OS was duration of initial remission, with patients who had an initial remission >1 year having much worse outcomes overall (response rate 74% vs. 25%, EFS 8% vs. 37% and OS of 16% vs. 39%, P < 0.01 for all). There was an acceptable toxicity profile with one neurological event and no cardiac events observed. The most common grade 3-4 toxicities observed were neutropenia (59%) and thrombocytopenia (68%). This study demonstrated that the novel combination of 2-CDA/Ida was effective and should be considered for incorporation in front line therapy for children with AML.     

Adult patients with t(8;21) acute myeloid leukemia had no superior treatment outcome to those without t(8;21): a single institution’s experience

Clinical features and treatment outcome of 31 patients over 16 years of age with t(8;21) acute myeloid leukemia (AML) were compared with 60 patients without t(8;21). Among 31 patients with t(8;21), 15 patients were classified as AML-M2 and 11 and 5 patients as AML-M4 and M1, respectively. Of these patients, 28 patients (90.3%) achieved complete remission and 22 patients received consolidative treatment: intermediate-dose cytarabine (IDAC) 11, high-dose cytarabine (HDAC) 6, and allogeneic bone marrow transplantation (BMT) 5. When compared with patients without t(8;21), we could not demonstrate better treatment outcome for t(8;21) AML [median event-free survival (EFS) and overall survival (OS) 10.3 and 12.5 months in AML with t(8;21) vs 11.5 and 15.6 months in AML without t(8;21)]. In the t(8;21) AML group, patients who received HDAC consolidation did not show superior treatment outcome to those who received other consolidative treatment [median EFS: IDAC 11.9 months vs HDAC 9.2 months vs allogeneic BMT 38.1 months (P=NS) and median OS: IDAC 17.8 months vs HDAC 12.0 months vs allogeneic BMT 47.3 months (P=NS)]. Similar treatment outcome between patients with and without t(8;21) and non-superior treatment outcome of HDAC consolidative chemotherapy in the t(8;21) AML group in our study is contradictory to previous reports.These two authors equally contributed to this study: K.-W. Lee and I. S. ChoiSupported by a grant CRI-01-07 from the Cancer Research Institute, Seoul National University College of Medicine, and a grant 05-2001-002 from the S.N.U.H. Research Fund     

Induction chemotherapy followed by allogeneic bone marrow transplantation or aggressive consolidation chemotherapy in childhood acute myeloblastic leukemia: A prospective study from the French Society of Pediatric Hematology and Immunology (SHIP)

In the LAME89/91 protocol, children with acute myeloid leukemia (AML) who achieved complete remission (CR) after induction chemotherapy, were treated either with allogeneic bone marrow transplantation (BMT) if they had an HLA-compatible related donor or with chemotherapy including high-dose cytarabine. The objectives of this study were to describe the overall results of this strategy and to compare the two post-remission arms. Two hundred and thirty-one children were enrolled in the protocol. Induction chemotherapy consisted of a combination of cytarabine and mitoxantrone. A CR was achieved in 204 children (88%). Fifty-one of them had an HLA-identical sibling donor and were eligible for BMT. These 51 patients, as well as two additional children who had a one antigen HLA-mismatched father, received BMT during first CR. Consequently, 53 patients were analysed in the BMT group and 151 in the chemotherapy group. With a mean follow up duration in the study of 38 ± 2 months, overall event-free survival (EFS) was 47 ± 7% at 4 years for the 231 patients entered into the protocol. The 4-year disease-free survival (DFS) was 53 ± 8% for the 204 patients who achieved complete remission after induction therapy. The 4-year probability of relapse was 28 ± 14% in the BMT group and 47 ± 9% in the chemotherapy group (p = 0.02). The risk of therapy-related death was 6.2% for BMT and 8.1% for chemotherapy. DFS was 68 ± 14% in the BMT group and 48 ± 9% in the chemotherapy group (p = 0.02). We conclude that allogeneic BMT from a matched sibling donor is the treatment of choice for reducing the relapse risk and for increasing DFS in children with AML in first CR.     

Fludarabine,cytarabine, and attenuated‐dose idarubicin (m‐FLAI) combination therapy for elderly acute myeloid leukemia patients

We performed a phase II trial to evaluate the efficacy and safety of the modified fludarabine, cytarabine, and attenuated‐dose idarubicin (m‐FLAI) regimen in elderly acute myeloid leukemia (AML) patients. Elderly (≥60 years) AML patients who had not previously received chemotherapy were enrolled in the study. Patients received two consecutive cycles of m‐FLAI chemotherapy as an induction. The m‐FLAI regimen comprised fludarabine (25 mg/m², days 1–4), cytarabine (1,000 mg/m², days 1–4), and attenuated‐dose idarubicin (5 mg/m², days 1–3). The primary end point was complete remission (CR) rate. Secondary end points were overall survival (OS), event‐free survival (EFS), and treatment‐related mortality (TRM). There were 108 patients (median age 68.4 years, M:F = 64:44) enrolled in the study. CR was achieved in 56.5% of patients, and the TRM rate was 21.3%. Median OS and median EFS were 10.2 and 6.6 months, respectively. The mortality at 30 and 60 days was 15 and 21%, respectively. Performance status and comorbidity did not have prognostic value in this patient cohort. Bone marrow expression of CD117 was associated with increased EFS and OS. m‐FLAI is an effective induction regimen for previously untreated AML in elderly patients. In addition, bone‐marrow CD117 expression is an independent favorable prognostic factor in elderly AML patients. (ClinicalTrials.gov number, NCT01247493). Am. J. Hematol. 2013. © 2012 Wiley Periodicals, Inc.     

Radiation-free regimens result in similar outcomes of allogeneic hematopoietic progenitor cell transplantation in patients aged >or=50 years compared to younger adults with low-risk disease

Age >or=50 years has been reported to be an adverse risk factor for allogeneic BMT, and consequently many of these patients are either not transplanted or treated on nonmyeloablative protocols. To study if older patients perform poorly relative to younger adults following myeloablative allogeneic transplants, we compared the outcomes of consecutive adults aged >or=50 years (n=51) to those <50 years (n=262) who received BU, CY+/-etoposide and allogeneic transplantation for AML, CML, MDS and NHL from 1984 to 2000. Median ages were 53 (range 50-66) and 35 (range 18-49) years for older and younger patients, respectively. Patients were low-risk if they had AML in CR1, CML in first chronic phase, refractory anemia, or NHL in remission or sensitive relapse at the time of transplantation. All others were high-risk. In patients with low-risk disease, there was no significant difference in overall survival (OS) between older and younger adults (P=0.64), while older patients tended to have a shorter OS among high-risk patients (P=0.06). The 3-year OS was 53% (95% CI, 29-77%) compared to 60% (95% CI, 50-69%) for older and younger patients with low-risk disease, respectively. The corresponding 3-year OS were 27% (95% CI, 11-43%) and 37% (95% CI, 25-45%) for high-risk patients. In low-risk patients, the incidence of acute and chronic graft-versus-host disease, and treatment-related mortality were similar in older and younger patients, while older patients experienced more treatment-related deaths by day 100. On multivariable analysis, age >or=50 years was a significant adverse factor only when high-risk patients were considered. We conclude that when radiation-free conditioning is used, age >or=50 years is not a significant adverse risk factor for allogeneic BMT in patients with low-risk disease, and that such patients should not be excluded from conventional myeloablative approaches until the efficacy of nonmyeloablative transplantation is better established.     

The value of the MDR1 reversal agent PSC-833 in addition to daunorubicin and cytarabine in the treatment of elderly patients with previously untreated acute myeloid leukemia (AML), in relation to MDR1 status at diagnosis

To determine whether MDR1 reversal by the addition of the P-glycoprotein (P-gp) inhibitor PSC-833 to standard induction chemotherapy would improve event-free survival (EFS), 419 untreated patients with acute myeloid leukemia (AML) aged 60 years and older were randomized to receive 2 induction cycles of daunorubicin and cytarabine with or without PSC-833. Patients in complete remission were then given 1 consolidation cycle without PSC-833. Neither complete response (CR) rate (54% versus 48%; P = .22), 5-year EFS (7% versus 8%; P = .53), disease-free survival (DFS; 13% versus 17%; P = .06) nor overall survival (OS; 10% in both arms; P = .52) were significantly improved in the PSC-833 arm. An integrated P-gp score (IPS) was determined based on P-gp function and P-gp expression in AML cells obtained prior to treatment. A higher IPS was associated with a significantly lower CR rate and worse EFS and OS. There was no significant interaction between IPS and treatment arm with respect to CR rate and survival, indicating also a lack of benefit of PSC-833 in P-gp-positive patients. The role of strategies aimed at inhibitory P-gp and other drug-resistance mechanisms continues to be defined in the treatment of patients with AML.     

Long-term outcome after intensive therapy with etoposide, melphalan, total body irradiation and autotransplant for acute myeloid leukemia

Intensive therapy and autologous blood and marrow transplantation (ABMT) is an established post-remission treatment for acute myeloid leukemia (AML), although its exact role remains controversial and few data are available regarding longer-term outcomes. We examined the long-term outcome of patients with AML transplanted at a single center using uniform intensive therapy consisting of etoposide, melphalan and TBI. In all, 145 patients with AML underwent ABMT: 117 in first remission, 21 in second remission and seven beyond second remission. EFS and OS were significantly predicted by remission status (P<0.0001). For transplantation in first remission, 8 year EFS and OS were 55% (95% CI, 44-64%) and 62% (95% CI, 50-72%), respectively. By multivariate analysis, only age (P=0.04) and cytogenetic risk group (P=0.006) influenced OS. For patients transplanted in second remission, 8 year EFS and OS were 30% (95% CI, 9-55%) and 36% (95% CI, 13-60%), respectively. No pre-transplant variables significantly predicted outcome. None of the seven patients who underwent ABMT beyond second remission or in early relapse were long-term survivors. ABMT can provide long-term antileukemic control for patients with AML in first remission. For patients in second remission approximately 30% can achieve cure with ABMT, and this option may be preferable to alternate donor allogeneic stem cell transplantation.     

Nonablative versus reduced-intensity conditioning regimens in the treatment of acute myeloid leukemia and high-risk myelodysplastic syndrome: dose is relevant for long-term disease control after allogeneic hematopoietic stem cell transplantation

Intensity of the preparative regimen is an important component of allogeneic transplantations for myelodysplasia (MDS) or acute myelogenous leukemia (AML). We compared outcomes after a truly nonablative regimen (120 mg/m2 fludarabine, 4 g/m2 cytarabine, and 36 mg/m2 idarubicin [FAI]) and a more myelosuppressive, reduced-intensity regimen (100 to 150 mg/m2 fludarabine and 140 or 180 mg/m2 melphalan [FM]). We performed a retrospective analysis of 94 patients with MDS (n = 26) and AML (n = 68) treated with FM (n = 62) and FAI (n = 32). The FAI group had a higher proportion of patients in complete remission (CR) at transplantation (44% versus 16%, P =.006), patients in first CR (28% versus 3%, P =.008), and HLA-matched sibling donors (81% versus 40%, P =.001). Median follow-up is 40 months. FM was significantly associated with a higher degree of donor cell engraftment, higher cumulative incidence of treatment-related mortality (TRM; P =.036), and lower cumulative incidence of relapse-related mortality (P =.029). Relapse rate after FAI and FM was 61% and 30%, respectively. Actuarial 3-year survival rate was 30% after FAI and 35% following FM. In a multivariate analysis of patient- and treatment-related prognostic factors, progression-free survival was improved after FM, for patients in CR at transplantation, and for those with intermediate-risk cytogenetics. Survival was improved for patients in CR at transplantation. In conclusion, FM provided better disease control though at a cost of increased TRM and morbidity.     

A prognostic model for prolonged event-free survival after autologous or allogeneic blood or marrow transplantation for relapsed and refractory Hodgkin's disease

There are several prognostic models for Hodgkin's disease (HD) patients, but none evaluating patient characteristics at time of blood and marrow transplantation (BMT). We developed a prognostic model for event-free survival (EFS) post-BMT based on HD patient characteristics measured at the time of autologous (auto) or allogeneic (allo) BMT. Between 1/1991 and 12/2001, 64 relapsed or refractory HD patients received an auto (n=46) or allo (n=18) BMT. A multivariate prognostic model was developed measuring time to relapse, progression or death. Median follow-up was 51.7 months; median EFS for auto and allo BMT was 36 and 3 months, respectively (P=0.001). Significant multivariate predictors of shorter EFS were chemotherapy-resistant disease, KPS <90 and > or =3 chemotherapy regimens pre-BMT. Patients with two to three adverse factors had significantly shorter EFS at 2 years (58 vs 11% in auto; 38 vs 0% in allo BMT patients). Despite a selection bias favoring auto BMT, the model was valid in both auto and allo BMT groups. We were able to differentiate patients at high vs low risk for adverse outcomes post-BMT. This prognostic model may prove useful in predicting patient outcomes and identifying high-risk patients for novel treatment strategies. Validation of this model in a larger cohort of patients is warranted.     

Hematopoietic stem cell transplantation in Lebanon: first comprehensive report

Hematopoietic SCT (HSCT) has become a curative therapeutic strategy for several malignant and nonmalignant diseases. We report the comprehensive results of the first 10 years of experience in HSCT from the two major BMT units in Lebanon: Makassed University Hospital and the American University of Beirut Medical Center. The median and the 5-year overall survival (OS) were 97 months and 58%, respectively, for the 84 patients who received allogeneic HSCT, and 60 months and 50%, respectively, for the 228 patients who received autologous BMT. The results for myeloablative allogeneic transplantation were as follows: AML (n=28, 5-year OS 58%, 5-year disease-free survival (DFS) 48%), CML (n=9, 5-year OS 66%, 5-year DFS 52%), ALL (n=13, 2-year OS 10%, 2-year DFS 10%), thalassemia (n=10, 5-year transfusion-free survival 67%). The results for autologous HSCT were as follows: diffuse large B-cell lymphoma (DLBCL) in relapse (n=37, 5-year OS 68%, 5-year progression-free survival (PFS) 65%), Hodgkin's lymphoma (n=55, 5-year OS 55%, 5-year PFS 36%), and first-line multiple myeloma (n=71, 5-year OS 53%, 5-year PFS 24%). For allogeneic transplanted patients, the cumulative TRM was 23% and the incidence of acute GVHD was 23%. For autografted patients, TRM was 2.6%. These results indicate that despite the relatively low socioeconomic status of the Lebanese population, both allogeneic and autologous HSCT are feasible with outcomes similar to developed countries.     

Early blast clearance by remission induction therapy is a major independent prognostic factor for both achievement of complete remission and long-term outcome in acute myeloid leukemia: data from the German AML Cooperative Group (AMLCG) 1992 Trial

Risk assessment in acute myeloid leukemia (AML) using pretreatment characteristics may be improved by incorporating parameters of early response to therapy. In the 1992 trial of the German AML Cooperative Group (AMLCG), the amount of residual leukemic blasts in bone marrow was assessed one week after the first induction course (day 16 blasts). A total of 449 patients 16 to 76 years of age (median, 53 years) with de novo AML entered the trial and were evaluable. Treatment included TAD/HAM (thioguanine, cytosine arabinoside, and daunorubicin/high-dose cytosine arabinoside and mitoxantrone) double induction, TAD consolidation, and randomly either maintenance therapy or S-HAM consolidation. Cytogenetics were favorable, intermediate, unfavorable and not available in 10.0%, 48.3%, 13.1%, and 28.5%, respectively. Day 16 blasts ranged from 0% to 100% (median, 5%, mean +/- SD, 18.6 +/- 28.5%). Complete remission (CR) rate was 72.6%, 17.6% had persistent leukemia (PL), and 9.8% succumbed to hypoplastic death. Median overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS) were 18, 9, and 15 months with 28.4%, 21.6%, and 30.1% at 5 years, respectively. As a continuous variable, day 16 blasts were related to CR rate (P < 0.0001), PL rate (P < 0.0001), OS (P < 0.0001), EFS (P < 0.0001), and RFS (P = 0.0049). Multivariate analyses identified the following parameters to be associated with the respective end points. CR rate: day 16 blasts (P <.0001), age (P =.0036), and LDH (P =.0072); OS: unfavorable cytogenetics (P <.0001), day 16 blasts (P <.0001), age (P <.0001), and LDH (P =.0040); EFS: unfavorable cytogenetics (P <.0001), LDH (P <.0001), day 16 blasts (P <.0001), and age (P =.0061); RFS: unfavorable cytogenetics (P <.0001), LDH (P <.0001), and day 16 blasts (P =.0359). The prognostic significance of day 16 blasts is independent of pretherapeutic parameters and predicts outcome even in patients achieving a CR.     

Increasing dose intensity of anthracycline antibiotics improves outcome in patients with acute myelogenous leukemia

To understand the effect of dose concentration in the overall survival of AML, we conducted a study on the efficacy and toxicity of a drug combination where the dose of daunorubicin was intensified. For this analysis, the outcome of patients entered into two consecutive prospective trials was compared. Inclusion criteria in both arms were identical and consisted of primary AML in adults. Treatment protocol for Cape Town Regimen 4 (CTR-IV) comprised of cytarabine infusion (100 mg/m(2)) and etoposide (100 mg/m(2)), injection daily for 7 days in combination with daunorubicin (45 mg/m(2)) on days 1, 2, and 3. Patients achieving remission were given two further courses of the same chemotherapy and received allogeneic or autologous transplantation. CTR-V was a similar treatment program, except that daunorubicin was escalated on days 1, 2, and 3 to 75 mg/m(2) during induction and to 60 mg/m(2) during a single consolidation. Patients were also offered stem cell transplantation. Between 1990 and 1997, 78 patients (median age 33; range 13-67 years) fulfilled entry criteria and received CTR-IV. From 1998 onwards, 35 patients (median age 36; range 15-66 years) were prospectively enlisted into the CTR-V trial. The patient population in CTR-V had fewer Caucasian individuals (P = 0.02) and had significantly lower presentation hemoglobin (P = 0.0002). Following initiation of induction chemotherapy, 40 patients failed to respond. Among these, 10 patients demised before day 28. Another 30 (25/69 CTR-IV and 5/32 in CTR-V groups; P = 0.01) had leukemia that was resistant to chemotherapy, and all died. Remission was achieved in 59% of patients treated with CTR-IV and 77% of those receiving CTR-V (P = 0.03). CR occurred with a single course in 64% versus 88% (P = 0.02), respectively. There were no differences in the toxicity profile between these two combinations. Disease recurred in 50% and 28% (P = 0.07) of patients. For the 113 individuals, median follow up is 254 (range 19-4,451) and 304 (12-1,702; P = 0.03) days. Survival is 23% and 40%, respectively, favoring patients treated with CTR-V (log rank; P = 0.03). Cox regression analysis showed that treatment group (P < 0.001), FAB type, hemoglobin level, and platelet count were independent factors for response to chemotherapy. Older age and not undergoing myeloablative therapy were the only adverse factors for survival. We conclude that increase in the treatment dose of daunorubicin in patients with AML led to a higher remission rate, particularly with a single course of chemotherapy and had an equivalent toxicity profile. This therapeutic modification is also likely to result in substantial reduction in patient stay in hospital and in the overall expenditure.     

Ifosphamide, etoposide and epirubicin is an effective combined salvage and peripheral blood stem cell mobilisation regimen for transplant-eligible patients with non-Hodgkin lymphoma and Hodgkin disease

A total of 143 patients with relapsed (n = 90), primary refractory (n = 32) and first line chemotherapy responsive (n = 21) non-Hodgkin lymphoma (NHL) and Hodgkin disease (HD) were treated with IVE (ifosphamide, etoposide and epirubicin) chemotherapy with the intent to proceed to high-dose therapy with either autologous or allogeneic transplantation, following peripheral blood stem cell mobilisation. A major response (complete/partial response) to IVE was seen in 115 patients (80.4%) with 5-year overall survival (OS) and event free survival (EFS) of 53% and 43%, respectively. Subgroup analysis showed overall response rates of 93.1% for HD with a 5-year OS and EFS of 62% and 52% respectively, while NHL showed response rates of 78.0% with 5-year OS and EFS of 50% and 39% respectively. The median number of CD34 +ve cells mobilised following IVE was 7.86 x 10(6) (range 1.72-42.91 x 10(6)), with 60% mobilising >2 x 10(6)/kg in a single collection. Grade IV neutropenia was seen in 79.6% patients and 77/270 cycles required intravenous antibiotic treatment. We conclude that IVE has a high response rate across a range of refractory and relapsed lymphoma with acceptable toxicity and excellent PBSC mobilising characteristics.